Low daily MEWS scores as predictors of low-risk hospitalized patients.

BACKGROUND: The Modified Early Warning System (MEWS) is a well-validated tool used by hospitals to identify patients at high risk for an adverse event to occur. However, there has been little evaluation into whether a low MEWS score can be predictive of patients with a low likelihood of an adverse event. AIM: The present study aims to evaluate the MEWS score as a method of identifying patients at low risk for adverse events. DESIGN: Retrospective cohort study of 5676 patient days and analysis of associated MEWS scores, medical comorbidities and adverse events. The primary outcome was the association of average daily MEWS scores in those who had an adverse event compared with those who did not. RESULTS: Those with an average MEWS score of >2 were over 9 times more likely to have an adverse event compared with those with an average MEWS score of 1-2, and over 15 times more likely to have an adverse event compared to those with an average MEWS score of <1. CONCLUSIONS: Our study shows that those with average daily MEWS scores <2 are at a significantly lower likelihood of having an adverse event compared with a score of >2, deeming them 'low-risk patients'. Formal recognition of such patients can have major implications in a hospital setting, including more efficient resource allocation in hospitals and better patient satisfaction and safety by adjusting patient monitoring according to their individual risk profile.

Benchmarking an 11-qubit quantum computer.

The field of quantum computing has grown from concept to demonstration devices over the past 20 years. Universal quantum computing offers efficiency in approaching problems of scientific and commercial interest, such as factoring large numbers, searching databases, simulating intractable models from quantum physics, and optimizing complex cost functions. Here, we present an 11-qubit fully-connected, programmable quantum computer in a trapped ion system composed of 13 171Yb+ ions. We demonstrate average single-qubit gate fidelities of 99.5[Formula: see text], average two-qubit-gate fidelities of 97.5[Formula: see text], and SPAM errors of 0.7[Formula: see text]. To illustrate the capabilities of this universal platform and provide a basis for comparison with similarly-sized devices, we compile the Bernstein-Vazirani and Hidden Shift algorithms into our native gates and execute them on the hardware with average success rates of 78[Formula: see text] and 35[Formula: see text], respectively. These algorithms serve as excellent benchmarks for any type of quantum hardware, and show that our system outperforms all other currently available hardware.

Ultrafast creation of large Schrödinger cat states of an atom.

Mesoscopic quantum superpositions, or Schrödinger cat states, are widely studied for fundamental investigations of quantum measurement and decoherence as well as applications in sensing and quantum information science. The generation and maintenance of such states relies upon a balance between efficient external coherent control of the system and sufficient isolation from the environment. Here we create a variety of cat states of a single trapped atom's motion in a harmonic oscillator using ultrafast laser pulses. These pulses produce high fidelity impulsive forces that separate the atom into widely separated positions, without restrictions that typically limit the speed of the interaction or the size and complexity of the resulting motional superposition. This allows us to quickly generate and measure cat states larger than previously achieved in a harmonic oscillator, and create complex multi-component superposition states in atoms.Generation of mesoscopic quantum superpositions requires both reliable coherent control and isolation from the environment. Here, the authors succeed in creating a variety of cat states of a single trapped atom, mapping spin superpositions into spatial superpositions using ultrafast laser pulses.

Active stabilization of ion trap radiofrequency potentials.

We actively stabilize the harmonic oscillation frequency of a laser-cooled atomic ion confined in a radiofrequency (rf) Paul trap by sampling and rectifying the high voltage rf applied to the trap electrodes. We are able to stabilize the 1 MHz atomic oscillation frequency to be better than 10 Hz or 10 ppm. This represents a suppression of ambient noise on the rf circuit by 34 dB. This technique could impact the sensitivity of ion trap mass spectrometry and the fidelity of quantum operations in ion trap quantum information applications.

Sensing Atomic Motion from the Zero Point to Room Temperature with Ultrafast Atom Interferometry.

We sense the motion of a trapped atomic ion using a sequence of state-dependent ultrafast momentum kicks. We use this atom interferometer to characterize a nearly pure quantum state with n=1 phonon and accurately measure thermal states ranging from near the zero-point energy to n[over ¯]~10^{4}, with the possibility of extending at least 100 times higher in energy. The complete energy range of this method spans from the ground state to far outside of the Lamb-Dicke regime, where atomic motion is greater than the optical wavelength. Apart from thermometry, these interferometric techniques are useful for characterizing ultrafast entangling gates between multiple trapped ions.

Beat note stabilization of mode-locked lasers for quantum information processing.

We stabilize a chosen radio frequency beat note between two optical fields derived from the same mode-locked laser pulse train in order to coherently manipulate quantum information. This scheme does not require access or active stabilization of the laser repetition rate. We implement and characterize this external lock, in the context of two-photon stimulated Raman transitions between the hyperfine ground states of trapped 171Yb(+) quantum bits.

Effects of the dual PPAR-α/γ agonist aleglitazar on glycaemic control and organ protection in the Zucker diabetic fatty rat.

AIMS: To evaluate the effects of aleglitazar, a dual peroxisome proliferator-activated receptor-α/γ agonist, on the development of diabetes-related organ dysfunction, in relation to glycaemic and lipid changes, in Zucker diabetic fatty (ZDF) rats. METHODS: Six-week-old, male ZDF rats received aleglitazar 0.3 mg/kg/day or vehicle as food admix for 13 weeks (n = 10 per group). Age-matched male Zucker lean rats served as non-diabetic controls. Plasma and renal markers were measured at several time points. Histopathology and quantitative immunohistochemistry were performed at 13 weeks. RESULTS: Glycated haemoglobin (5.4 vs. 9.2%) and blood glucose (8.3 ± 0.3 vs. 26.1 ± 1.0 mmol/l) were significantly reduced at 12 weeks with aleglitazar versus vehicle-treated ZDF rats (both p < 0.01), while aleglitazar preserved near-normal plasma insulin levels. Aleglitazar prevented the development of hypertriglyceridaemia (1.4 ± 0.1 vs. 8.5 ± 0.9 mmol/l) and reduced plasma non-esterified fatty acids (0.09 ± 0.02 vs. 0.26 ± 0.04 mmol/l) relative to vehicle-treated animals (both p < 0.01). Urinary glucose and protein concentrations were significantly reduced at 13 weeks with aleglitazar versus vehicle-treated rats (both p < 0.01). Consistent with its effect on glycaemic control, aleglitazar protected ß-cell morphology, as evidenced by preservation of islet integrity, and reduction of ß-cell apoptosis and islet fibrosis. Aleglitazar prevented renal glomerular hypertrophy, podocyte degeneration, glomerulosclerosis, tubulo-interstitial lesions and development of cataracts. CONCLUSIONS: Aleglitazar strongly improved glycaemic and lipid parameters while protecting key tissues, including the pancreas, kidneys and eyes, against diabetes-associated structural and functional changes in the ZDF rat.

Ultrafast spin-motion entanglement and interferometry with a single atom.

We report entanglement of a single atom's hyperfine spin state with its motional state in a time scale of less than 3 ns. We engineer a short train of intense laser pulses to impart a spin-dependent momentum transfer of ± 2 hk. Using pairs of momentum kicks, we create an atomic interferometer and demonstrate collapse and revival of spin coherence as the motional wave packet is split and recombined. The revival after a pair of kicks occurs only when the second kick is delayed by an integer multiple of the harmonic trap period, a signature of entanglement and disentanglement of the spin with the motion. Such quantum control opens a new regime of ultrafast entanglement in atomic qubits.

Ultrafast gates for single atomic qubits.

We demonstrate single-qubit operations on a trapped atom hyperfine qubit using a single ultrafast pulse from a mode-locked laser. We shape the pulse from the laser and perform a π rotation of the qubit in less than 50 ps with a population transfer exceeding 99% and negligible effects from spontaneous emission or ac Stark shifts. The gate time is significantly shorter than the period of atomic motion in the trap (Ω(Rabi)/ν(trap)>10(4)), demonstrating that this interaction takes place deep within the strong excitation regime.

Entanglement of atomic qubits using an optical frequency comb.

We demonstrate the use of an optical frequency comb to coherently control and entangle atomic qubits. A train of off-resonant ultrafast laser pulses is used to efficiently and coherently transfer population between electronic and vibrational states of trapped atomic ions and implement an entangling quantum logic gate with high fidelity. This technique can be extended to the high field regime where operations can be performed faster than the trap frequency. This general approach can be applied to more complex quantum systems, such as large collections of interacting atoms or molecules.

Reduced plaque formation induced by rosiglitazone in an STZ-diabetes mouse model of atherosclerosis is associated with downregulation of adhesion molecules.

Adhesion molecules have been implicated in the development and progression of cardiovascular disease, which is highly prevalent in people with diabetes. Adhesion molecules can mediate adhesion of leukocytes to the endothelium. Furthermore, P-selectin expressed on platelets is able to mediate the adhesion of leukocytes to platelets. In this study, we examine the in-vivo and in-vitro effects of rosiglitazone with particular emphasis on three important adhesion molecules (VCAM-1, ICAM-1 and P-selectin). In the aorta of STZ-diabetic apolipoprotein E-deficient (apoE KO) mice, rosiglitazone significantly reduced both total and arch plaque area. The mechanism for this appeared to be reduced macrophage infiltration into the atherosclerotic plaque which was also associated with reduced mRNA levels for VCAM-1, ICAM-1, MCP-1 and P-selectin in the aorta. In-vitro studies revealed reduced cell adhesion of monocytic cells (THP-1) to fibrinogen and endothelial cells (HUVEC) after incubation with rosiglitazone. Furthermore, the reduction in leukocyte adhesion also correlated with significant reductions in mRNA levels for VCAM-1, ICAM-1 and P-selectin indicating that reduced macrophage infiltration in atherosclerotic plaques may occur as a result of a direct effect of rosiglitazone on adhesion molecules in both monocytes and endothelial cells. Thus, we have shown that rosiglitazone appears to have direct anti-atherosclerotic effects in an animal model of diabetes-associated atherosclerosis which are at least partly due to effects on VCAM-1, ICAM-1, MCP-1 and P-selectin expression which leads to decreased leukocyte adhesion and macrophage infiltration.

Effect of selective fatiguing of the shank muscles on single-leg-standing sway.

Control of standing requires the continuous activity of the leg muscles. In single leg standing the system is less redundant and muscular activity is more intensive. The objective of this study was to examine the effect of force imbalance of the shank muscles, evoked by their selective fatiguing, on postural control in single-leg standing. Five healthy subjects performed two single-leg standing trials, lasting as long as the subject could maintain steady balance, and separated by a 240s quasi-isotonic sustained effort to induce fatigue of the Tibialis Anterior and Peroneus muscles. The following were on-line monitored: sway-related parameters, e.g., ground reaction force and center of pressure in the standing trials; and electromyogram of the Tibialis Anterior, Peroneus and Gastrocnemius muscles in all experiments. Simple and multiple linear regressions served to study the fatigue effects on the relationship between muscle activity and postural sway. The results indicate that the evoked muscle imbalance leads to (a) increased postural sway; (b) increased correlation between muscle activity, and sway-related parameters. Thus, with the reduction of the level of redundancy the system becomes more synchronized. These results have potential relevance for cases of muscle impairment, in which electrical stimulation is required to augment muscle activity.

PPARs and diabetes-associated atherosclerosis.

Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors affecting the regulation of various genes relevant to the pathogenesis of diabetic complications. A number of drugs have been developed to act as agonists of the three PPARs. To date, PPAR isoforms that have been identified are the alpha, beta/delta, and gamma isosforms. Fenofibrate and gemfibrozil are two drugs that act as PPARalpha agonists and are currently in use in the clinical setting. Rosiglitazone is a PPARgamma agonist also in clinical use. These drugs have proved very useful in regulation of either glucose or lipid metabolism and consequently are used in patients with type 2 diabetes. Here, we will review the anti-atherosclerotic potential of PPAR agonists with particular emphasis on recent studies in an animal model of diabetes-associated atherosclerosis, the streptozotocin diabetic apolipoprotein E deficient mouse. These studies have shown both PPARalpha agonists, gemfibrozil and fenofibrate, confer anti-atherosclerotic effects, partly independent of their metabolic effects. Similar positive findings have also been detected in a dose-dependent manner with the PPARgamma agonist, rosiglitazone. The potential clinical implications of these findings are also discussed in view of the recently reported results of the PROACTIVE and FIELD clinical trials with the PPAR agonists rosiglitazone and fenofibrate respectively.

Muscle enhancement using closed-loop electrical stimulation: volitional versus induced torque.

In cases of partial deficiency of muscle activation capacity, force augmentation can be achieved by hybrid activation, i.e., by combining electrical stimulation (ES) with volitional activation. In this activation modality the shares of the volitional and induced torques within the overall hybrid torque are unknown. The purpose of this study was to suggest a computational approach to parcel out the volitional and stimulation induced components of joint torque generated during combined voluntary and electrical activation of the Tibialis Anterior muscle (TA). For this purpose, isometric contraction of the TA was studied on 5 healthy subjects, using an activation protocol involving ES alone, volitional activation alone and hybrid activation. Ankle torque and TA EMG were measured. A computational algorithm was developed to dissociate the volitional from the overall torque, based on EMG filtering and on pre-measured calibration curves of volitional torque versus EMG. The results indicated that for a certain hybrid torque there is a linear decaying relationship between the induced torque and the volitional torque shares. Moreover, based on a defined enhancement ratio, the results indicate that within the range of stimulation intensities, there exist regions of increased facilitation, in which the stimulation efficiency is higher under combined compared to isolated conditions.

Synthesis and biological evaluation of novel hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazines as potent and selective 5-HT(2C) receptor agonists.

Further lead optimization efforts on previously described 1,2,3,4,10,10a-hexahydro-1H-pyrazino[1,2-a]indoles led to the new class of 5,5a,6,7,8,9-hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazines culminating in the discovery of (5aR,9R)-2-[(cyclopropylmethoxy)methyl]-5,5a,6,7,8,9-hexahydro-9-methyl-pyrido[3', 2':4,5]pyrrolo[1,2-a]pyrazine 18 as a potent, full 5-HT(2C) receptor agonist with an outstanding selectivity profile and excellent hERG and phospholipidosis properties.

Identification of 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT2C receptor agonists.

Synthesis and evaluation of the activity of new 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT(2C) receptor agonists are described. Appropriately substituted, several analogs displayed selectivity against the other 5-HT(2) receptor subtypes of 1 order of magnitude or more. Selectivity was improved for several compounds versus the lead 1, increasing the therapeutic interest in this series of 5-HT(2C) receptor agonists.

Transmission-line model for myelinated nerve fiber.

Herein, the well-known cable equation for non-myelinated axon model is extended analytically for myelinated axon formulation. The classical cable equation is thereby modified into a linear second order ordinary differential equation with periodic coefficient, known as Hill's equation. Hill's equation exhibits periodic solutions, known as Floquet's modes. The Floquet's modes are recognized as the nerve fiber activation modes, which are conventionally associated with the nonlinear Hodgkin-Huxley formulation. They can also be incorporated in our linear model.

Muscle force augmentation by low-intensity electrical stimulation.

In cases of muscle partial deficiency, force augmentation can be achieved by hybrid activation, i.e., by combining electrical stimulation (ES) with volitional activation. In the present study the volitional and electrically-induced torque components are resolved under visual-feedback activation. Isometric contraction of the tibialis anterior (TA) muscle was studied on 5 healthy subjects, using an activation protocol combining ES alone, volitional activation alone and hybrid activation. Ankle torque and TA EMG were measured. A computational algorithm was developed to dissociate the volitional from the overall torque, based on EMG filtering and on pre-measured calibration curves of volitional torque versus EMG. Based on a defined facilitation factor, the results indicate that within the range of stimulation intensities, there exist regions of increased facilitation of the volitional activation of the TA muscle, in which the torque contribution due to the induced activation is higher compared that of the recruitment curve.

Effects of anorexinogen agents on cloned voltage-gated K(+) channel hKv1.5.

Appetite suppressants have been associated with primary pulmonary hypertension (PPH), inhibition of voltage-gated potassium channels, membrane depolarization, and calcium entry in pulmonary artery smooth muscle cells. In cells taken from pulmonary arteries of primary pulmonary hypertensive patients, voltage-gated potassium channels appear to be dysfunctional and in particular, reduced hKv1.5 gene transcription and hKv1.5 mRNA instability have been shown. We have compared the effects of anorexinogen agents on hKv1.5 channels stably expressed in mammalian cell line. We found that aminorex, phentermine, dexfenfluramine, sibutramine, and fluoxetine cause a dose-dependent inhibition of hKv1.5 current. Aminorex, phentermine, and dexfenfluramine had a K(D) of inhibition greater than to 300 microM and are not potent inhibitors of hKv1.5. Sibutramine and fluoxetine inhibited hKv1.5 current with lower K(D) values of 41 and 21 microM, respectively. Block by both drugs increased rapidly between -20 and +10 mV, coincident with channel opening and suggested an open channel block mechanism. This was confirmed by a slower deactivation time course resulting in a "crossover" phenomenon when tail currents recorded under control conditions and in the presence of either drug were superimposed. Single channel experiments demonstrated that open probability and open duration of hKv1.5 were decreased by fluoxetine and sibutramine. These results indicate that among the anorexinogen agents tested, sibutramine and fluoxetine are the most potent toward hKv1.5 channel, which they preferentially block in the open state. Nevertheless, their inhibitory effects do not correlate with their ability to produce PPH neither with their previously reported therapeutic plasma concentrations.

Fatigue-induced changes in decline running.

OBJECTIVE: Study the relation between muscle fatigue during eccentric muscle contractions and kinematics of the legs in downhill running. DESIGN: Decline running on a treadmill was used to acquire data on shock accelerations, muscle activity and kinematics, for comparison with level running. BACKGROUND: In downhill running, local muscle fatigue is the cause of morphological muscle damage which leads to reduced attenuation of shock accelerations. METHODS: Fourteen subjects ran on a treadmill above level-running anaerobic threshold speed for 30 min, in level and -4 degrees decline running. The following were monitored: metabolic fatigue by means of respiratory parameters; muscle fatigue of the quadriceps by means of elevation in myoelectric activity; and kinematic parameters including knee and ankle angles and hip vertical excursion by means of computerized videography. Data on shock transmission reported in previous studies were also used. RESULTS: Quadriceps fatigue develops in parallel to an increasing vertical excursion of the hip in the stance phase of running, enabled by larger dorsi flexion of the ankle rather than by increased flexion of the knee. CONCLUSIONS: The decrease in shock attenuation can be attributed to quadriceps muscle fatigue in parallel to increased vertical excursion of the hips.